The melanocortins represent a group of peptides which derive from the same precursor, proopiomelanocortin (POMC), and which are structurally similar: adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), β-MSH and γ-MSH (Eipper B. A. and Mains R. E., Endocr. Rev. 1980, 1, 1-27). The melanocortins perform numerous physiological functions. They stimulate the synthesis of steroids by the adrenal cortex and the synthesis of eumelanin by the melanocytes. They regulate food intake, energy metabolism, sexual function, neuronal regeneration, blood pressure and heart rate, as well as pain perception, learning, attention and memory. The melanocortins also possess anti-inflammatory and anti-pyretic properties and control the secretion of several endocrine or exocrine glands such as the sebaceous, lachrymal, mammary glands, the prostate and the pancreas (Wikberg J. E. et al., Pharmacol. Res. 2000, 42, 393-420; Abdel-Malek Z. A., Cell. Mol. Life. Sci. 2001, 58, 434-441).
The effects of the melanocortins are mediated by a family of membrane receptors specific to seven transmembrane domains and G-protein-coupled. Five receptor subtypes, named MC1 to MC5, have been cloned and characterized to date. These receptors differ in their tissue distribution and affinity for the different melanocortins, the MC2 receptors recognizing only ACTH. The stimulation of the melanocortin receptors activates the adenylate cyclase with production of cyclic AMP. If the functional roles specific to each of the receptors are not totally elucidated, the treatment of pathological disorders or diseases can be associated with an affinity for certain subtypes of receptors. Thus the activation of the MC1 receptors has been associated with the treatment of inflammations, whereas blocking them has been associated with the treatment of cutaneous cancers. The treatment of nutritional disorders has been associated with the MC3 and MC4 receptors, the treatment of obesity by the agonists and the treatment of cachexia and anorexia by the antagonists. Other indications associated with the activation of the MC3 and MC4 receptors are sexual activity disorders, neuropathic pain, anxiety, depression and drug addiction. The activation of the MC5 receptors has been associated with the treatment of acne and dermatitis.
The applicants have found that the novel compounds of general formula (I) described hereafter possess a good affinity for the melanocortin receptors. They act preferentially on the MC4 receptors. Said compounds, melanocortin receptor agonists or antagonists, can be used in order to treat pathological states or metabolic diseases, of the nervous or dermatological system in which one or more melanocortin receptors are involved such as the following examples: inflammatory states, energy homeostasis disorders, food intake disorders, weight disorders (obesity, cachexia, anorexia), sexual activity disorders (erectile disorders), pain and more particularly neuropathic pain. Mental disorders can also be mentioned (anxiety, depression), drug addiction, skin diseases (acne, dermatitis, cutaneous cancers, melanomas). These compounds can also be used for stimulating nerve regeneration.